The resolution of inflammation is a central component of host defense and the return of tissue to homeostasis (4). It is recognized that inflammation plays a key role in many prevalent human diseases including cardiovascular diseases, atherosclerosis, Alzheimer's disease, and cancer (5-7). Although much is known about the molecular basis of initiating signals and proinflammatory chemical mediators in inflammation, it has only recently become apparent that endogenous stop signals are critical at early checkpoints within the temporal events of inflammation (8). In this context, lipid mediators are of interest. The arachidonic acid-derived prostaglandins and leukotrienes are potent pro-inflammatory mediators (9), whereas their cousins, the lipoxins, biosynthesized from arachidonic acid, are potent anti-inflammatory and proresolving molecules (for reviews see 10, 11, 12). During the course of inflammation, arachidonate-derived eicosanoids switch from prostaglandins and leukotrienes within inflammatory exudates to lipoxins that in turn stop the recruitment of neutrophils to the site. This switch in eicosanoid profiles and biosynthesis is driven, in part, by cyclooxygenase-derived prostaglandin E2 and prostaglandin D2, which instruct the transcriptional regulation of enzymes involved in lipoxin biosynthesis (13). Hence, the appearance of lipoxins within inflammatory exudates is concomitant with spontaneous resolution of inflammation (13), and these chemical mediators are non-phlogistic stimulators of monocyte recruitment and macrophage phagocytosis of apoptotic PMN (14, 15)
Further studies on the endogenous mechanisms of anti-inflammation using a murine model of spontaneous resolution demonstrated, for the first time, that resolution is an active biochemical process that involves the generation of specific new families of lipid mediators (for recent reviews, see refs. 16, 17). During spontaneous resolution, cell-cell interactions and transcellular biosynthesis lead to the production of these new families of potent bioactive lipid mediators from ω-3 essential fatty acid precursors and were termed resolvins (resolution phase interaction products derived from DHA and EPA) and protectins (docosatrienes derived from DHA) ((1, 3, 18) and recently reviewed in (19)). These novel di- and trihydroxy-containing products from EPA and DHA that are generated by previously unrecognized enzymatic pathways display potent anti-inflammatory and immunoregulatory actions in vitro and in vivo in murine models of acute inflammatory actions (1, 3, 18).
In 1929, the omega-3 polyunsaturated fatty acids were assigned essential roles because their exclusion from the diet gave rise to a new form of deficiency disease (20). Many recent reports document the importance of fish oil (omega-3) fatty acids EPA and DHA in human diseases associated with inflammation. In particular, omega-3 DHA and EPA are protective in inflammatory bowel disease and colitis (21), cardiovascular disease (22-25), and Alzheimer's disease (26). However, the molecular mechanisms responsible for these documented beneficial actions of omega-3 fatty acids remain an important challenge. DHA is enriched in neural tissues, where it appears to play functional as well as structural roles (27, 28). Along these lines, results from earlier studies indicated that DHA was enzymatically converted to products coined docosanoids that might be linked to retinal protection (29) and neuronal function (30). The structures of the molecules involved, however, were not established.
Human whole blood isolated leukocytes, and glial cells enzymatically convert DHA to 17S-hydroxy-containing docosatrienes and 17S-series resolvins (1, 3). The novel 10,17S-docosatriene, first identified in ref. (3) and its basic structure established, displayed potent anti-inflammatory actions, i.e., reducing PMN numbers in exudates in vivo, and down regulating production of proinflammatory cytokines by glial cells in vitro (1). During the resolution phase of peritonitis, unesterified DHA levels increase within exudates and 10,17S-docosatriene is generated within the resolving exudates, where it appears to promote catabasis, or the return to homeostasis, by shortening the resolution interval (31). Of special interest, this DHA-derived 10,17S-docosatriene is generated in vivo during strokes in murine tissues and limits the entry of leukocytes into the area of neural damage, reducing the magnitude of tissue injury (32). It was found that 10,17S-docosatriene is neuroprotective in retinal pigmented cells and introduced the term neuroprotectin D1 for this potent compound (2), which accumulates in the ipsilateral hemisphere of the brain following focal ischemia (33).
Recent results indicate that neuroprotectin D1 is formed from DHA in cornea in a lipoxygenase-dependent fashion to protect from thermal injury as well as promote wound healing (34). It is noteworthy that neuroprotectin D1, resolvin D1, and resolvin D5 are all produced by trout brain cells from endogenous DHA, suggesting that the structures of these DHA-derived mediators are conserved from fish to humans (35). Together, these recent findings underscore the need to establish the complete stereochemistry of endogenous biologically active 10,17S-docosatriene, namely its carbon 10 position alcohol chirality and double bond geometry of its conjugated triene system. In recognition of its wide scope of formation and actions, protectin D1 (PD1) is used to denote the structure of this chemical mediator and the prefix neuro before protectin D1 is used to note its tissue origin and address. Here, the complete stereochemistry of protectin D1 and its related natural isomers (i.e., Δ15-trans-PD1) as well as their anti-inflammatory properties are reported.
Therefore, a need exists for additional understanding of how other polyunsaturated compounds and biological derivative may provide insight into such complex biological pathways.